Characterizing the role of the structural connectome in seizure dynamics

Abstract

How does the human brain’s structural scaffold give rise to its intricate functional dynamics? This is a central question in translational neuroscience that is particularly relevant to epilepsy, a disorder affecting over 50 million subjects worldwide. Treatment for medication-resistant focal epilepsy is often structural—through surgery or laser ablation—but structural targets, particularly in patients without clear lesions, are largely based on functional mapping via intracranial EEG. Unfortunately, the relationship between structural and functional connectivity in the seizing brain is poorly understood. In this study, we quantify structure-function coupling, specifically between white matter connections and intracranial EEG, across pre-ictal and ictal periods in 45 seizures from nine patients with unilateral drug-resistant focal epilepsy. We use high angular resolution diffusion imaging (HARDI) tractography to construct structural connectivity networks and correlate these networks with time-varying broadband and frequency-specific functional networks derived from coregistered intracranial EEG. Across all frequency bands, we find significant increases in structure-function coupling from pre-ictal to ictal periods. We demonstrate that short-range structural connections are primarily responsible for this increase in coupling. Finally, we find that spatiotemporal patterns of structure-function coupling are highly stereotyped for each patient. These results suggest that seizures harness the underlying structural connectome as they propagate. Mapping the relationship between structural and functional connectivity in epilepsy may inform new therapies to halt seizure spread, and pave the way for targeted patient-specific interventions.

Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy

“…One possibility is that elements of seizure networks are activated during interictal states (43); thus, seizures with different network features could be preceded by preictal periods with corresponding network structures. Researchers could also relate preictal/interictal networks to other seizure features, such as seizure propagation patterns, perhaps by investigating how the underlying structural connectome relates to functional networks (64) and mediates seizure spread (63). Importantly, the relationship between preictal network dynamics and seizure features could be limited to a specific frequency band (23), which could in turn suggest possible physiological mechanisms for the observed changes in seizure dynamics (65,66).…”

Pairwise maximum entropy model explains the role of white matter structure in shaping emergent co-activation states

“…Since iEEG datasets from healthy controls do not exist, we cannot directly address these concerns. Nevertheless, we draw on recent work demonstrating that the patterns of iEEG functional connectivity in patients show statistical similarities to structural connectivity estimated in healthy volunteers 52 , and that this statistical similarity is upheld and even strengthened during ictal epochs 59,60 . Future work using data from patients with other pathologies, or using source-localized MEG in healthy patients, could be helpful in further understanding the nature of the structure-function correspondence accessible to the MEM.…”

“…The observed high degree of structure-function coupling suggests that structural connectivity is a useful proxy for time-invariant functional relationships 52,59 . This observation could be useful in the treatment of epilepsy patients, where access to the brain is traditionally limited to recording loci but could be augmented with non-invasive measurements of structural connectivity for more informed surgical planning 60 . Indeed, it is intuitively plausible that computational models built to inform the modulation of abnormal functional dynamics via stimulation 61 or resection 62 may be able to utilize patient-specific structural connectivity in place of or to augment patient-specific functional connectivity.…”

High interictal connectivity within the resection zone is associated with favorable post-surgical outcomes in focal epilepsy patients

“…Recent evidence indicates that seizures most commonly arise from abnormal brain networks rather than isolated focal lesions (Bernhardt et al, 2013; Kramer and Cash, 2012; Shah et al, 2019). Therefore, in order to accurately map seizure generation, it is important to identify brain network abnormalities in epilepsy.…”